• Friday, Jul 10, 2020
  • Last Update : 04:05 pm

Is remdesivir the answer?

  • Published at 12:00 am June 4th, 2020
remdesivir drung covid-19
Our best shot so far? REUTERS

There is currently no medication shown to prevent or cure Covid-19, according to WHO

On April 10 this year, the New England Journal of Medicine (NEJM) published an article: “Compassionate use of Remdesivir for patients with severe Covid-19.” The study was supported by Gilead Sciences, the manufacturer of the drug. Gilead Sciences provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. 

Patients were those with confirmed SARS-CoV-2 infection, who were RT-PCR positive for SARS-CoV-2, with an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. 53 patients had treatment with remdesivir and their data were analyzed. 22 of the patients were from the United States, nine from Japan, 12 from Italy, four from France, two from Germany, and one each from Austria, Netherlands, Spain, and Canada.

The study was designed and conducted by the sponsor, Gilead Sciences, manufacturer of remdesivir, who collected the data, monitored the conduct of the program and performed the statistical analyses. 

All authors had access to the data and assumed responsibility for the integrity and completeness of the reported data. The initial draft of the manuscript was prepared by a writer employed by Gilead Sciences along with one of the authors, with input from all the authors.

The majority of patients, 34 (64%) were receiving invasive ventilation, including 30 (57%) receiving mechanical ventilation and 4 (8%) receiving extracorporeal membrane oxygenation. The study concluded the improvement of patients after remdesivir treatment. 

The quality of the study and the statistical analysis used appear to be pretty weak as it was not a randomized, controlled, or blinded study and no sample-size calculations were performed. 

Associations between pre-treatment characteristics and clinical improvement and mortality outcomes were evaluated with a simple analytical model. However, the analysis did not include a provision for correcting for multiple comparisons in tests for the association between baseline variables and outcomes. 

Though the 95% confidence interval was used as part of the statistical analysis, it was advised by the sponsor/authors not to use the confidence interval to infer definitive associations with outcomes as the widths of the confidence intervals were not adjusted for multiple comparisons in the analysis.

The study claims an improvement of patient’s condition in 84% of cases without the benefit of control, improvement appears to happen more in patients having non-invasive ventilator support than invasive, again without the benefit of comparing, and mortality of 13%. 32 patients (60%) reported adverse events during follow-up. 

The most common adverse events were increased hepatic enzymes, diarrhoea, rash, renal impairment, and hypotension. Most importantly one in four patients (23%) had serious adverse events of a multi-organ-dysfunction syndrome, septic shock, acute kidney injury, and significant hypotension.         

Remdesivir, a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models.

Prior to the article published in the New England Journal of Medicine, a randomized, double-blind, placebo-controlled, multicentre trial was conducted at 10 hospitals in Hubei, China. 

Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to the enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia.

Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir, 200mg on day one followed by 100mg on days 2-10 in single daily infusions or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. 

The primary analysis was done in the intention-to-treat population, and safety analysis was done in all patients who started their assigned treatment. Between February 6 and March 12 this year 237 patients were enrolled and randomly assigned to a treatment group, 158 to remdesivir, and 79 to placebo. 

In the study, remdesivir use was not associated with a difference in time to clinical improvement. Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo if the drug was started within 10 days or less of starting to become symptomatic. 

Adverse events were reported in 102 (66%) of remdesivir recipients versus 50 (64%) of placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. 

In this study of adult patients admitted to hospital for severe Covid-19, remdesivir was not associated with statistically significant clinical benefits. However, the study concluded that the numerical reduction in the time to clinical improvement in those treated earlier required confirmation in larger studies.

This study was the first randomized, double-blind, placebo-controlled clinical trial assessing the effect of intravenous remdesivir in adults admitted to hospital with severe Covid-19. However, the study was terminated before attaining the pre-specified sample size. 

In the intention-to-treat population, the primary endpoint of time to clinical improvement was not significantly different between groups, but was numerically shorter in the remdesivir group than the control group, particularly in those treated within 10 days of symptom onset. 

The duration of invasive mechanical ventilation, although also not significantly different between groups, was numerically shorter in remdesivir recipients than placebo recipients. No statistically significant benefits were observed for remdesivir treatment beyond those of standard care treatment. 

The critics of the trial mention that the study did not attain the predetermined sample size because the outbreak of Covid-19 was brought under control in China. 

However, future studies of remdesivir, including earlier treatment in patients with Covid-19 and higher-dose regimens or in combination with other antivirals or SARS-CoV-2 neutralizing antibodies in those with severe Covid-19, are needed to better understand its potential effectiveness.

In its latest statement on treatment for Covid-19, the WHO recommends that there are no medicines that have been shown to prevent or cure the disease. WHO does not recommend self-medication with any medicines as a prevention or cure for Covid-19. However, there are several ongoing clinical trials of both Western and traditional medicines. 

WHO is the main organization coordinating efforts to develop vaccines and medicines to prevent and treat Covid-19, and is committed to delivering the most contemporary research-based information as and when they become available.

The existing published literature on the drugs claimed to be beneficial in treatment and prevention of present coronavirus infection including remdesivir, are observational in nature with few clinical trials and do not provide high-quality evidence in favour of any of the medications.

Intensifying the complexity of the use of these therapeutic agents are added extraneous factors of side effects and substantial adversity inherent to the drugs. Remdesivir is known to be associated with a substantial number of patients with vital and multi-organ failure, kidney impairment, and hypotensive shock.

WHO’s recommendation remains unchanged and is consistent with previous WHO guidance documents and other international grade-based guidelines. However, WHO advises that outside of clinical trials, investigational therapeutics such as remdesivir can be considered for treatment as no proven effective treatment for Covid-19 exists. 

But only if the clinical trial is not feasible to be started immediately, if intervention’s preliminary efficacy and safety information extracted from laboratory or animal studies is available and the drug is recommended by expert scientific advisory committee fulfilling certain defined criteria, if the country’s appropriate authority has approved after availability of resource with risk minimalization has been ensured, the informed consent of the patient is obtained, and the patient understands the full implication of the therapy. 

Formal and full clinical documentation of the therapeutic intervention, monitoring of results, and sharing of the result with the wider medical and scientific community are the mandatory pre-conditions of the use of these medications. 

Dr Raqibul Mohammad Anwar is a Specialist Surgeon and Global Health Policy and Planning Expert, and Retired Colonel, Royal Army Medical Corps, UK Armed Force.

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